The invention relates to the field of immunology. The invention in particular relates to the role of dendritic cells in immune responses and to pathogens that are able to capitalize thereon.
Dendritic cells (DC) are professional antigen presenting cells (APC) that induce cellular immunity upon pathogen recognition. These cells are therefore important in the defense against many pathogens1;2;3. Immature DC are seeded throughout peripheral tissues to act as sentinels against invading pathogens4. Upon pathogen capture, DC are activated, process pathogens for antigen presentation on Major Histocompatability Complex (MHC) class II molecules, and migrate to the secondary lymphoid organs where they activate naive T cells to initiate adaptive immune responses1;3;4. Depending on the pathogen that is recognized by the DC, differentiation of naive T cells into Th1 cells is triggered by DC in response to intracellular microbes, whereas Th2-mediated responses are generated by DC to eliminate pathogens residing extracellularly3. Thus DC play an important role in both innate and cellular immune responses against tumors antigens as well as pathogens such as viral, bacterial, fungal and parasitic infections1;5. Knowledge about cell-surface receptors on DC that are involved in recognition of pathogens is only starting to emerge, and include Toll-like receptors (TLR)6;7 and C-type lectins8. TLR recognize specific pathogen-derived components, such as lipoproteins, lipopolysaccharides and bacterial DNA, and relay this information through intracellular signaling cascades leading to the production of regulatory cytokines and upregulation of MHC and costimulatory molecules that lead to activation/maturation of DC6. In contrast, C-type lectins recognize pathogen-derived carbohydrate structures and upon binding internalize pathogens for antigen processing and presentation to T cells8-10. In classical calcium-dependent lectins, conserved amino acid residues in the carbohydrate recognition domain (CRD) are involved in calcium binding and sugar specificity11. A growing number of C-type lectins are described to be specifically expressed by DC. For most of these lectins detailed knowledge about pathogen-targets as well as cellular ligands if any, including the identity of the carbohydrate structure they recognize, is lacking8. The DC-specific C-type lectin DC-SIGN (dendritic-cell specific ICAM-3 grabbing nonintegrin, CD209) is involved in binding of the HIV-1 envelope glycoprotein by DC to enhance infection of T cells12, while the mannose receptor (MR) is involved in recognition of mycobacteria and Fungi/Protozoa13, Some C-type lectins like DC-SIGN can interact with carbohydrate-bearing self glycoproteins (ICAM-2 and ICAM-3) to mediate cellular adhesion processes14;15.